Stem Cell Factor Programs the Mast Cell

Mast cells, activated by Ag via Fc«RI, release an array of proinflammatory mediators that contribute to allergic disorders, such as asthma and anaphylaxis. The KIT ligand, stem cell factor (SCF), is critical for mast cell expansion, differentiation, and survival, and under acute conditions, it enhances mast cell activation. However, extended SCF exposure in vivo conversely protects against fatal Ag-mediated anaphylaxis. In investigating this dichotomy, we identified a novel mode of regulation of the mast cell activation phenotype through SCF-mediated programming. We found that mouse bone marrow-derived mast cells chronically exposed to SCF displayed a marked attenuation of Fc«RI-mediated degranulation and cytokine production. The hyporesponsive phenotype was not a consequence of altered signals regulating calcium flux or protein kinase C, but of ineffective cytoskeletal reorganization with evidence implicating a downregulation of expression of the Src kinase Hck. Collectively, these findings demonstrate a major role for SCF in the homeostatic control of mast cell activation with potential relevance to mast cell-driven disease and the development of novel approaches for the treatment of allergic disorders. A ntigen-mediated mast cell (MC) activation, via FcεRI, results in the release of an array of inflammatory mediators that underlies allergic reactions in atopic disease (1, 2). MCs are derived from bone marrow progenitors that migrate into the circulation and peripheral tissues where they expand and mature under the influence of cytokines contained within the surrounding milieu (3). KIT activation, as a consequence of binding of its ligand stem cell factor (SCF) produced within tissues by stromal cells, is critical for the development of MCs from bone marrow progenitor cells and their subsequent accumulation, maturation, and survival in tissues (4). Unlike human MCs (5), mouse MC development and survival in culture are supported by IL-3 in the absence of SCF (6). However, the supplementary presence of SCF markedly enhances the rate of growth of these cells and is described to skew the development of the cells to that of a serosal/connective tissue phenotype. In contrast, cells grown in IL-3 alone are considered to more resemble the mucosal phenotype based on the types of proteases expressed (7–10). Little is known about how SCF and other extrinsic factors, or the combination thereof, may dictate the MC phenotype with regard to responsiveness to Ag and other stimulants. Under acute experimental conditions, SCF is one of several endogenous agents known to potentiate Ag-mediated MC degranulation and cytokine production (11–13). Nevertheless, in contrast …